Treatment of affective disorders by the combined action of a nicotinic receptor agonist and a monoaminergic substance

ABSTRACT

The use of the combined action of a nicotinic acetylcholine receptor agonist and a monoaminergic substance for the treatment of affective disorders, as well as pharmaceutical compositions comprising these substances and chemical substances for use in such treatment.

This application is a divisional of application Ser. No. 11/782,385,filed Jul. 24, 2007, which in turn is a divisional of application Ser.No. 10/380,653, filed Mar. 17, 2003. application Ser. No. 10/380,653 isthe national phase under 35 U.S.C. §371 of international applicationPCT/DK01/00661, filed Oct. 10, 2001, which designated the United Statesof America and which claims priority from Danish applicationPA2000-01535, filed Oct. 13, 2000, and from U.S. provisional applicationSer. No. 60/242,146, filed Oct. 23, 2000. The disclosures of theforegoing applications are incorporated by reference herein.

TECHNICAL FIELD

This invention relates to use of the combined action of a nicotinicacetylcholine receptor agonist and a monoaminergic substance for thetreatment of affective disorders, as well as to pharmaceuticalcompositions comprising these substances and chemical substances for useaccording to the invention.

BACKGROUND ART

Selective monoamine reuptake inhibitors, and in particular serotoninreuptake inhibitors (SSRI's), are the gold standard for treatingdepression. However, their most severe drawback is that while the sideeffects set in almost immediately, no substantial antidepressant effectwill be seen within the first 2 to 4 weeks, leaving a window ofvulnerability during which the patient might be non-compliant withtherapy. While co-administration of fast-acting antidepressants mayovercome this, it is more preferable to counteract the self-inhibitorymechanism that delays onset of SSRI effects.

There are good indications that this may be achieved by blocking certainreceptors that down-regulate the discharge of serotonin as theconcentration of neurotransmitter in the synaptic cleft rises. Thus WO96/33710 (Astra) describes a combination of a 5-HT uptake inhibitor witha selective 5-HT_(1A) antagonist, and WO 00/15217 (AstraZeneca), WO00/15218 (AstraZeneca) and WO 00/15219 (AstraZeneca) disclose specificexamples of such combinations.

Another combination involving nicotinic ligands, however for a quitedifferent use, is disclosed in WO 00/45846 (Synthelabo). This patentpublication describes the use of nicotine or a nicotinic ligand incombination with a monoamine oxidase (MAO) inhibitor for the treatmentof tobacco withdrawal symptoms, which combination shows reducedcardiovascular side effects.

Finally WO 00/25783 (Carlsson & Carlsson) describes the use of anicotinic receptor agonist in the treatment of obsessive compulsivedisorder (OCD). A combination therapy and the treatment of otheraffective disorders are not described.

SUMMARY OF THE INVENTION

According to the invention it has now been found that the action of anicotinic acetylcholine receptor agonist potentiate the monoaminergicaction, so the combination of a nicotinic acetylcholine receptor agonistand a monoamine agonist or antagonist or a monoamine reuptake inhibitorfor use in the treatment of affective disorders may result in a fasteronset of action and an increased success rate. The invention thereforeresides in the combined action of a nicotinic acetylcholine receptoragonist and a monoamine agonist or antagonist or a monoamine reuptakeinhibitor, or the dual action of a substance possessing both nicotinicacetylcholine receptor agonist activity and monoamine agonist orantagonist activity or monoamine reuptake inhibiting activity, for thetreatment of affective disorders.

Accordingly, in its first aspect, the invention provides a method oftreatment, prevention or alleviation of an affective disorder, diseaseor condition in a subject, which method comprises administering to saidsubject a therapeutically effective amount of one or more compoundshaving nicotinic acetylcholine agonistic activity and monoamineagonistic or antagonistic or reuptake inhibiting activity.

In another aspect the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a nicotinicacetylcholine agonist and a monoamine reuptake inhibitor, together withat least one pharmaceutically acceptable carrier or diluent.

In a third aspect the invention relates to the use of a nicotinicacetylcholine agonist and a monoamine reuptake inhibitor for themanufacture of a medicament for the treatment, prevention or alleviationof an affective disorder, disease or condition in a subject.

In quite another aspect the invention provides nicotinic acetylcholineagonist represented by Formula I

wherein

n is 1, 2 or 3; and

m is 0, 1 or 2; and

R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, acylor benzyl; and

R¹ represents 5-bromo-3-pyridyl; 5-bromo-3-pyridyl; 6-chloro-3-pyridyl;6-bromo-5-methoxy-3-pyridyl; 6-bromo-3-pyridyl;6-bromo-5-chloro-3-pyridyl; 5,6-dibromo-3-pyridyl;6-chloro-5-bromo-3-pyridyl; 6-iodo-5-methoxy-3-pyridyl;5,6-dichloro-3-pyridyl; 5-bromo-6-chloro-2-pyrazinyl;6-bromo-5-etynyl-3-pyridyl; 6-chloro-5-methoxy-3-pyridyl;6-phenyl-3-pyridazinyl; 6-chloro-2-pyrazinyl; 6-chloro-3-pyridazinyl;6-iodo-3-pyridazinyl; 6-(1-benzimidazolyl)-3-pyridazinyl; 2-pyrazinyl;6-chloro-2-pyrazinyl; 6-phenyl-3-pyridyl; 5-chloro-6-phenyl-3-pyridyl;5-chloro-6-methyl-3-pyridyl; 5-etynyl-3-pyridyl; 5-bromo-3-pyridyl;5-methoxy-6-bromo-3-pyridyl; 6-bromo-3-pyridyl;5-chloro-6-bromo-3-pyridyl; 5,6-dibromo-3-pyridyl;5-bromo-6-chloro-3-pyridyl; 5-methoxy-6-iodo-3-pyridyl; or5,6-dichloro-3-pyridyl.

In still another aspect the invention provides8-azabicyclo[3.2.1]oct-2-ene derivatives represented by Formula VI,

any of its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof;

wherein

R is hydrogen, alkyl, alkenyl, cycloalkyl, cyanoalkyl, phenyl, naphthylor benzyl; and

R¹ is

wherein R² is hydrogen, alkyl, cycloalkyl, or amino; or

furanyl, thienyl, pyrrolyl, oxazolyl, isoaxzolyl, imidazolyl, pyridyl,pyrimidinyl or thiazolyl, which heteroaryl group is optionallysubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, alkoxy, cyanoalkyl, halogen, CF₃, OCF₃,CN, amino, nitro, and furyl; or

naphthyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzothiazolyl, quinolinyl, isoquinolinyl or thieno-thienyl, whichbicyclic group is optionally substituted one or more times withsubstituents selected from the group consisting of alkyl, cycloalkyl,alkoxy, cyanoalkyl, halogen, CF₃, OCF₃, CN, amino, nitro and furyl.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

In its first aspect the present invention provides a method fortreatment, prevention or alleviation of an affective disorder, diseaseor condition in a subject, which method comprises administering to saidsubject a therapeutically effective amount of one or more compoundshaving nicotinic acetylcholine agonistic activity and monoamineagonistic or antagonistic or reuptake inhibiting activity.

The subject to be treated according to this invention is a living body,preferably a mammal, most preferably a human, in need for suchtreatment.

In a preferred embodiment, the therapeutically active substances areadministered as a combination therapy comprising a substance acting asnicotinic acetylcholine agonist and a substance acting as a monoamineagonist or antagonist or as a monoamine reuptake inhibitor.

In another preferred embodiment, the therapeutic effect is achievedusing a substance having the dual activity of a nicotinic acetylcholineagonist and a monoamine agonist or antagonist or a monoamine reuptakeinhibitor.

The affective disorder, disease or condition may in particular bedepression, anxiety, obsessive compulsive disorder (OCD), panicdisorder, obesity, symptoms arising from smoking cessation, or pain,including acute and chronic pain, neuropathic pain, and inflammatorypain.

Nicotinic Acetylcholine Agonists

The nicotinic acetylcholine agonist of the invention may be any ligandthat binds to and activates the nicotinic acetylcholine receptor,thereby resulting in a biological response. The potential of a givensubstance to act as a nicotinic acetylcholine agonist may be determinedusing standard in vitro binding assays and/or standard in vivofunctionality tests.

In a preferred embodiment the nicotinic acetylcholine agonist of theinvention show a Ki of less than 1000 nM, preferably less than 100 nM,when determined in a standard human nicotinic receptor ion channelbinding and or displacement assay, or an EC₅₀ or IC₅₀ value of less than300 μM, preferably less than 100 μM, when determined in a standardfunctionality assay using a mouse, rat, or human nicotinic receptor ionchannel, which ion channel is preferably composed of a combination ofα₂₋₉ and β₂₋₄ nAChR subunits, or of homomers of α nAChR subunits.

Nicotinic acetylcholine agonist for use according to the inventioninclude those substances described in e.g. WO 92/21339 (Abbott), WO94/08992 (Abbott), WO 96/40682 (Abbott), WO 9746554 (Abbott), WO99/03859 (AstraZeneca), WO 96/15123 (Salk Institute) WO 97/19059(Sibia), WO 00/10997 (Ortho-McNeil), WO 00/44755 (Abbott), WO 00/34284(Synthelabo), WO 98/42713 (Synthelabo), WO 99/02517 (Synthelabo), WO00/34279 (Synthelabo), WO 00/34279 (Synthelabo), WO 00/34284(Synthelabo), EP 955301 (Pfizer), EP 857725 (Pfizer), EP 870768(Pfizer), EP 311313 (Yamanouchi Pharmaceutical), WO 97/11072 (NovoNordisk), WO 97/11073 (Novo Nordisk), WO 98/54182 (NeuroSearch), WO98/54181 (NeuroSearch), WO 98/54152 (NeuroSearch), WO 98/54189(NeuroSearch), WO 99/21834 (NeuroSearch), WO 99/24422 (NeuroSearch), WO00/32600 (NeuroSearch), WO PCT/DK00/00211 (NeuroSearch), WOPCT/DK00/00202 (NeuroSearch), or their foreign equivalents.

Examples of preferred nicotinic acetylcholine agonist according to theinvention include nicotine, ethyl nicotine,3-ethynyl-5-(1-methyl-2-pyrrolidinyl)pyridine (SIB-1765F),4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol (SIB-1553),(S)-3-ethynyl-5-(1-methyl-2-pyrrolidinyl)-pyridine (SIB-1508Y),4′-methylnicotine or (2S-trans)-3-(1,4-dimethyl-2-pyrrolidinyl)pyridine(Abbott), 2-methyl-3-[(2S)-2-pyrrolidinylmethoxy]-pyridine (ABT-089),3-methyl-5-[(2S)-1-methyl-2-pyrrolidinyl]-isoxazole (ABT-418),5-[(2R)-2-azetidinylmethoxy]-2-chloro-Pyridine (ABT-594), 3-PMP or3-(1-pyrrolidinylmethyl)pyridine (R J Reynold),(3E)-N-methyl-4-(3-pyridinyl)-3-buten-1amine (RJR-2403), anabasein or3,4,5,6-tetrahydro-2,3′-bipyridine (R J Reynold), 5-fluoronicotine or(S)-5-fluoro-3-(1-methyl-2-pyrrolidinyl)pyridine (R J Reynold), MCC or2-(dimethylamino)ethyl methylcarbamate (Lundbeck), ethyl arecolone or1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-propanone (Lilly), orisoarecolone or 1-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)ethanone(Lilly), AR-R17779 (AstraZeneca), epibatidine, GTS-21,1-(6-chloro-3-pyridyl)-homopiperazine, 1-(3-pyridyl)-homopiperazine,1-(5-ethynyl-3-pyridyl)-homopiperazine, or salts, free bases, racematesor enantiomers thereof.

Preferred Nicotinic Agonists

In a preferred embodiment the nicotinic acetylcholine agonist for useaccording to the invention are those disclosed in WO 99/21834represented by Formula I

any of its enantiomers or any mixture thereof, isotopes thereof or apharmaceutically acceptable salt thereof;

wherein

n is 1, 2 or 3; and

m is 0, 1 or 2; and

R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, acylor benzyl; and

R¹ represents 5-bromo-3-pyridyl; 5-bromo-3-pyridyl; 6-chloro-3-pyridyl;6-bromo-5-methoxy-3-pyridyl; 6-bromo-3-pyridyl;6-bromo-5-chloro-3-pyridyl; 5,6-dibromo-3-pyridyl;6-chloro-5-bromo-3-pyridyl; 6-iodo-5-methoxy-3-pyridyl;5,6-dichloro-3-pyridyl; 5-bromo-6-chloro-2-pyrazinyl;6-bromo-5-etynyl-3-pyridyl; 6-chloro-5-methoxy-3-pyridyl;6-phenyl-3-pyridazinyl; 6-chloro-2-pyrazinyl; 6-chloro-3-pyridazinyl;6-iodo-3-pyridazinyl; 6-(1-benzimidazolyl)-3-pyridazinyl; 2-pyrazinyl;6-chloro-2-pyrazinyl; 6-phenyl-3-pyridyl; 5-chloro-6-phenyl-3-pyridyl;5-chloro-6-methyl-3-pyridyl; 5-etynyl-3-pyridyl; 5-bromo-3-pyridyl;5-methoxy-6-bromo-3-pyridyl; 6-bromo-3-pyridyl;5-chloro-6-bromo-3-pyridyl; 5,6-dibromo-3-pyridyl;5-bromo-6-chloro-3-pyridyl; 5-methoxy-6-iodo-3-pyridyl; or5,6-dichloro-3-pyridyl.

In a more preferred embodiment, the compound for use according to theinvention is a chemical compound of Formula I, wherein

n and m are 1; and

R represents hydrogen, methyl, or 4-tert-butoxycarbonyl; and

R¹ represents 5-bromo-3-pyridyl; 5-bromo-3-pyridyl; 6-chloro-3-pyridyl;6-bromo-5-methoxy-3-pyridyl; 6-bromo-3-pyridyl;6-bromo-5-chloro-3-pyridyl; 5,6-dibromo-3-pyridyl;6-chloro-5-bromo-3-pyridyl; 6-iodo-5-methoxy-3-pyridyl;5,6-dichloro-3-pyridyl; 5-bromo-6-chloro-2-pyrazinyl;6-bromo-5-etynyl-3-pyridyl; 6-chloro-5-methoxy-3-pyridyl;6-phenyl-3-pyridazinyl; 6-chloro-2-pyrazinyl; 6-chloro-3-pyridazinyl;6-iodo-3-pyridazinyl; 6-(1-benzimidazolyl)-3-pyridazinyl; 2-pyrazinyl;6-chloro-2-pyrazinyl; 6-phenyl-3-pyridyl; 5-chloro-6-phenyl-3-pyridyl;5-chloro-6-methyl-3-pyridyl; 5-etynyl-3-pyridyl; 5-bromo-3-pyridyl;5-methoxy-6-bromo-3-pyridyl; 6-bromo-3-pyridyl;5-chloro-6-bromo-3-pyridyl; 5,6-dibromo-3-pyridyl;5-bromo-6-chloro-3-pyridyl; 5-methoxy-6-iodo-3-pyridyl; or5,6-dichloro-3-pyridyl.

In its most preferred embodiment, the compound of Formula I is

1-(5-bromo-3-pyridyl)-piperazine;

1-(6-chloro-3-pyridyl)-piperazine;

1-(6-bromo-5-methoxy-3-pyridyl)-piperazine;

1-(6-bromo-3-pyridyl)-piperazine;

1-(6-bromo-5-chloro-3-pyridyl)-piperazine;

1-(5,6-dibromo-3-pyridyl)-piperazine;

1-(6-chloro-5-bromo-3-pyridyl)-piperazine;

1-(6-iodo-5-methoxy-3-pyridyl)-piperazine;

1-(5,6-dichloro-3-pyridyl)-piperazine;

1-(5-bromo-6-chloro-2-pyrazinyl)-piperazine;

1-(6-bromo-5-etynyl-3-pyridyl)-piperazine;

1-(6-chloro-5-methoxy-3-pyridyl)-piperazine;

1-(6-phenyl-3-pyridazinyl)-piperazine;

1-(6-chloro-2-pyrazinyl)-piperazine;

1-(6-chloro-3-pyridazinyl)-piperazine;

1-(6-iodo-3-pyridazinyl)-piperazine;

1-[6-(1-benzimidazolyl)-3-pyridazinyl]-piperazine;

1-(2-pyrazinyl)-piperazine;

1-(6-chloro-2-pyrazinyl)-4-methyl-piperazine;

1-(6-phenyl-3-pyridyl)-piperazine;

1-(5-chloro-6-phenyl-3-pyridyl)-piperazine;

1-(5-chloro-6-methyl-3-pyridyl)-4-tert-butoxycarbonyl-piperazine; or

1-(5-etynyl-3-pyridyl)-piperazine;

or an enantiomer or a mixture of its enantiomers, or an isotope thereofor a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the compound for use according to theinvention is a chemical compound of Formula I, wherein

n is 2; and

m is 1; and

R represents hydrogen, methyl, or 4-tert-butoxycarbonyl; and

R¹ represents 5-bromo-3-pyridyl; 5-bromo-3-pyridyl; 6-chloro-3-pyridyl;6-bromo-5-methoxy-3-pyridyl; 6-bromo-3-pyridyl;6-bromo-5-chloro-3-pyridyl; 5,6-dibromo-3-pyridyl;6-chloro-5-bromo-3-pyridyl; 6-iodo-5-methoxy-3-pyridyl;5,6-dichloro-3-pyridyl; 5-bromo-6-chloro-2-pyrazinyl;6-bromo-5-etynyl-3-pyridyl; 6-chloro-5-methoxy-3-pyridyl;6-phenyl-3-pyridazinyl; 6-chloro-2-pyrazinyl; 6-chloro-3-pyridazinyl;6-iodo-3-pyridazinyl; 6-(1-benzimidazolyl)-3-pyridazinyl; 2-pyrazinyl;6-chloro-2-pyrazinyl; 6-phenyl-3-pyridyl; 5-chloro-6-phenyl-3-pyridyl;5-chloro-6-methyl-3-pyridyl; 5-etynyl-3-pyridyl; 5-bromo-3-pyridyl;5-methoxy-6-bromo-3-pyridyl; 6-bromo-3-pyridyl;5-chloro-6-bromo-3-pyridyl; 5,6-dibromo-3-pyridyl;5-bromo-6-chloro-3-pyridyl; 5-methoxy-6-iodo-3-pyridyl; or5,6-dichloro-3-pyridyl.

In its most preferred embodiment, the compound of Formula I is

1-(5-bromo-3-pyridyl)-homopiperazine;

1-(6-chloro-3-pyridyl)-homopiperazine;

1-(5-methoxy-6-bromo-3-pyridyl)-homopiperazine;

1-(6-bromo-3-pyridyl)-homopiperazine;

1-(5-chloro-6-bromo-3-pyridyl)-homopiperazine;

1-(5,6-dibromo-3-pyridyl)-homopiperazine;

1-(5-bromo-6-chloro-3-pyridyl)-homopiperazine;

1-(5-methoxy-6-iodo-3-pyridyl)-homopiperazine; or

1-(5,6-dichloro-3-pyridyl)-homopiperazine;

or an enantiomer or a mixture of its enantiomers, or an isotope thereofor a pharmaceutically acceptable salt thereof.

Monoaminergic Substances

The monoamine activity may be obtained using any monoaminergic substanceshowing monoamine agonistic or antagonistic or monoamine reuptakeinhibiting activity.

The monoamine reuptake inhibitor for use according to the invention mayin particular be a mixed monoamine reuptake inhibitor, anoradrenalin/dopamin uptake inhibitor, a classical tricyclicantidepressive agent, or a selective serotonin reuptake inhibitor(SSRI).

Serotonergic drugs for use according to the invention includeFenfluramine, Dexfenfluramine, Tryptophan, Chlorimipraqmine,Cyanimipramine, Fluoxetine, Paroxetine, Citalopram, Femoxitine,Cianopramine, Sertaline, Sibutramine, Venlafaxine, ORG 6582, RU 25591,LM 5008, DU 24565, Indalpine, CGP 6085/A, WY 25093, Alaprociate,Zimelidine, Trazodone, Amitriptyline, Imipramine, Desipramine,Mirtazapine, Trimipramine, Doxepin, Protriptylin, Nortriptylin,Dibenzoxazepine, Deprenyl, Isocarboxazide, Phenelzine, Tranylcypromine,Furazolidone, Procarbazine, Moclobemide, Brofaromin, Nefazodone,Bupropion, MK-212, DOI, m-CPP, RO 60-0175/ORG 35030, RO 60-0332/ORG35035, RO 60-0175, ORG 12962, RO 60-0332, α-methyl-5HT, TFMPP,Bufotenin, RU 24969, Quipazine, 5-carboxyamidotryptamine, Sumatripan,CGS 12066, 8-OH-DPAT,(S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine,(S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno(1,2-b)pyrrol-1-yl)-1-methyl-ethylamine,SB 206553, and pharmaceutically acceptable salts thereof.

Examples of preferred serotonergic agonistic drugs include MK-212, DOI,m-CPP, RO 60-0175/ORG 35030, RO 60-0332/ORG 35035, ORG 12962,(S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine,(S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno(1,2-b)pyrrol-1-yl)-1-methylethylamine,and SB 206553.

Examples of preferred of mixed monoamine reuptake inhibiting drugsinclude those described in WO 97/16451 (NeuroSearch) and WO 97/13770(NeuroSearch), or their foreign equivalents. The most preferred mixedmonoamine reuptake inhibiting drugs include(1S,3S,4S,5S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0]decan-5-ol.

Examples of preferred of NA/DA-uptake inhibitors include drugs likeVenlafaxin, Bupropion, Nomifensine, Minacipram, Reboxetin.

Examples of preferred of classic tricyclic antidepressiva include drugslike Imipramin, Amitriptyline, Clomipramine, Doxepin, Amoxapine,Desipramine, Maprotiline, Nortriptyline and Protriptyline.

In its most preferred embodiment the monoamine reuptake inhibitor of theinvention is a mixed monoamine reuptake inhibitor or a selectiveserotonin reuptake inhibitor (SSRI). Examples of preferred of SSRI'sinclude drugs like Norzimeldine, Fluoxetine, Clomipramine, Sertraline,Fluvoxamine, Alaproclate,(−)-trans-5-(4-p-fluorophenyl-3-piperidylmethoxy)-1.3-benzodioxole(Paroxetine), and1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile(Citalopram), and Nefazodone.

Chemical Substances of “Dual Action”

In another embodiment, the therapeutic effect is achieved using asubstance having the dual activity of a nicotinic acetylcholine agonistand a monoamine agonist or antagonist or a monoamine reuptake inhibitor.A chemical compound for use according to the invention having this dualactivity may in particular be a diazabicycloalkane derivative asdescribed in WO 00/66586 and in co-pending International PatentApplication No. PCT/DK01/00432, and represented by the general FormulaII

(II)

or a dimer thereof represented by any of Formulas III, IV or V

wherein,

n is 2; and

m is 1; and

one of R and R¹ represents hydrogen or alkyl; and

the other of R or R¹ represents a phenyl group, a naphthyl group or aquinolinyl group, which groups may be substituted once or twice withchloro, fluoro, trifluoromethyl, methoxy or trifluoromethoxy, and

B represents a bridging linker, e.g. ethyleneglycol.

In a more preferred embodiment the compound for use according to theinvention is a diazabicycloalkane derivative of Formula II, wherein

one of R or R¹ represents hydrogen or methyl, and

the other of R and R¹ represents 2-naphthalyl; 2-quinolinyl;3,4-dichlorophenyl; 6-quinolinyl; 4-fluorophenyl; 3-fluorophenyl;4-trifluoromethoxyphenyl; 3-trifluoromethoxyphenyl; phenyl; or3,4-dichlorophenyl.

In a most preferred embodiment the compound for use according to theinvention is a diazabicycloalkane derivative of Formula II, which is

(±)3-(2-naphthalyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane;

(±)3-(2-quinolinyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane;

(±)3-(3,4-dichlorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane;

(±)3-(6-quinolinyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane;

(±)3-(4-fluorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane;

(±)3-(3-fluorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane;

(±)3-(4-trifluoromethoxyphenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane;

(±)3-(3-trifluoromethoxyphenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane;

(±)3-(phenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane; or

(±)3-(3,4-dichlorophenyl)-9-H-3,9-diazabicyclo-[4.2.1-]-nonane;

or an enantiomer or a mixture of its enantiomers, or an isotope thereofor a pharmaceutically acceptable salt thereof.

In another preferred embodiment the compound for use according to theinvention is a diazabicycloalkane derivative of Formula IV or V, whichis

O,O″-bis-[5-(9-Methyl-3,9-diazabicyclo-[4.2.1]-nonan-3-yl)-3-pyridyl]-ethyleneglycol;

or an enantiomer or a mixture of its enantiomers, or an isotope thereofor a pharmaceutically acceptable salt thereof.

In yet another preferred embodiment the therapeutic effect is achievedusing a substance having the dual activity of a nicotinic acetylcholineagonist and a monoamine agonist or antagonist or a monoamine reuptakeinhibitor. A chemical compound for use according to the invention havingdual activity may in particular be an 8-azabicyclo[3.2.1]oct-2-enederivative of Formula VI,

any of its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof;

wherein

R is hydrogen, alkyl, alkenyl, cycloalkyl, cyanoalkyl, phenyl, naphthylor benzyl; and

R¹ is

wherein R² is hydrogen, alkyl, cycloalkyl, or amino; or

furanyl, thienyl, pyrrolyl, oxazolyl, isoaxzolyl, imidazolyl, pyridyl,pyrimidinyl or thiazolyl, which heteroaryl group is optionallysubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, alkoxy, cyanoalkyl, halogen, CF₃, OCF₃,CN, amino, nitro, and furyl; or

naphthyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzothiazolyl, quinolinyl, isoquinolinyl or thieno-thienyl, whichbicyclic group is optionally substituted one or more times withsubstituents selected from the group consisting of alkyl, cycloalkyl,alkoxy, cyanoalkyl, halogen, CF₃, OCF₃, CN, amino, nitro and furyl.

In a more preferred embodiment R of Formula VI represents hydrogen,methyl, ethyl, allyl, cyanomethyl, or benzyl; and

R¹ of Formula VI represents acetyl, 3-pyridyl, 3-(6-methoxy)pyridyl,3-(6-chloro)pyridyl, 2-thiazolyl, 3-thienyl, 2-thienyl,2-(3-methoxymethyl)thienyl, 2-(3-bromo)thienyl, 2-(3,4-dibromo)thienyl,2-furyl, 3-furyl, 2-(3-bromo)thienyl), 3-chlorothien-2-yl, 5-indolyl,3-(3-furyl)-2-thienyl, 3-quinolinyl, 3-benzofuryl, 2-benzofuryl,3-benzothienyl, 2-benzothienyl, 2-benzothiazolyl,2-thieno[3.2-b]thienyl, thieno[2.3-b]thienyl, 2-(3-bromo)benzofuryl or2-(3-bromo)benzothienyl.

In it most preferred embodiment the 8-azabicyclo[3.2.1]oct-2-enederivative of Formula VI is

(±)-3-(2-benzothienyl)-8-H-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-benzothienyl)-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-allyl-3-(2-benzothienyl)-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-allyl-3-(2-benzothienyl)-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-allyl-3-[2-(3-bromothienyl)]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-benzothienyl)-8-cyanomethyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3,4-dibromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or

(±)-3-(5-indolyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

or an enantiomer or a mixture of its enantiomers, or an isotope thereofor a pharmaceutically acceptable salt thereof.

Definition of Substituents

In the context of this invention halogen represents a fluorine, achlorine, a bromine or an iodine atom. Thus, a trihalogenmethyl grouprepresents e.g. a trifluoromethyl group, a trichloromethyl group andsimilar trihalogen-substituted methyl groups.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to eighteen carbon atoms (C₁₋₁₈-alkyl),more preferred of from one to six carbon atoms (C₁₋₆-alkyl; loweralkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyland isohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkylgroup, including butyl, isobutyl, secondary butyl, and tertiary butyl.In another preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to eight carbon atoms (C₂₋₈-alkenyl),more preferred of from two to six carbon atoms (C₂₋₆-alkenyl), includingat least one double bond. In a most preferred embodiment the alkenylgroup of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or3-butenyl, or 1,3-butdienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or1,3-hexdienyl, or 1,3,5-hextrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or7-octenyl, or 1,3-octdienyl, or 1,3,5-octtrienyl, or1,3,5,7-octtetraenyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

In the context of this invention a cycloalkyl-alkyl group designates acycloalkyl group as defined above, which cycloalkyl group is substitutedon an alkyl group as also defined above. Examples of preferredcycloalkyl-alkyl groups of the invention include cyclopropylmethyl andcyclopropylethyl.

In the context of this invention an alkoxy group designates an“alkyl-O—” group, wherein alkyl is as defined above.

In the context of this invention an acyl group designates a carboxygroup (—COOH) or an alkyl-carbonyl group (alkyl-CO—), wherein alkyl isas defined above. Examples of preferred acyl groups of the inventioninclude carboxy, acetyl, propionyl, and 4-tert-butoxycarbonyl.

Pharmaceutical Compositions

Viewed from another aspect the invention relates to the use of anicotinic acetylcholine agonist and a monoamine reuptake inhibitor forthe manufacture of a medicament for the treatment, prevention oralleviation of an affective disorder, disease or condition in a subject,including a human.

The pharmaceutical composition according to the invention thereforecomprises a therapeutically effective amount of a nicotinicacetylcholine agonist and a monoamine agonist or antagonist or monoaminereuptake inhibitor, together with at least one pharmaceuticallyacceptable carrier or diluent.

In a preferred embodiment, the pharmaceutical composition comprises asubstance acting as nicotinic acetylcholine agonist and a substanceacting as a monoamine agonist or antagonist or monoamine reuptakeinhibitor.

In another preferred embodiment, however, the pharmaceutical compositioncomprises a substance having the dual activity of a nicotinicacetylcholine agonist and a monoamine agonist or antagonist or monoaminereuptake inhibitor.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefore, and,optionally, other therapeutic and/or prophylactic ingredients, know andused in the art. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notharmful to the recipient thereof.

The pharmaceutical composition of the invention may be administered byany convenient route, which suits the desired therapy. Preferred routesof administration include oral administration, in particular in tablet,in capsule, in dragé, in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. The pharmaceutical composition may be prepared bythe skilled person using standard and conventional techniquesappropriate to the desired formulation. When desired, compositionsadapted to give sustained release of the active ingredient may beemployed.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

The pharmaceutical composition of the invention preferably is for use inthe treatment, prevention or alleviation of an affective disorder,disease or condition in a subject. The affective disorder, disease orcondition may in particular be depression, anxiety, obsessive compulsivedisorder (OCD), panic disorder, or pain.

The actual dosage depend on the nature and severity of the disease beingtreated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.01 to about 500 mg of active ingredient per individualdose, preferably of from about 0.1 to about 100 mg, most preferred offrom about 1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

Example 1 Preparatory Example General

All reactions involving air sensitive reagents or intermediates wereperformed under nitrogen and in anhydrous solvents. Magnesium sulphatewas used as drying agent in the workup-procedures and solvents wereevaporated under reduced pressure.

Method A

1-(5-Bromo-3-pyridyl)-piperazine Fumaric Acid Salt (Compound 1A1)

A mixture of 3,5-dibromopyridine (100 g, 422 mmol) and piperazine (72.7g, 844 mmol) was stirred at 130° C. for 100 hours. Water (400 ml) wasadded and the pH was adjusted to 7 by adding hydrochloric acid (4 M).The aqueous phase was washed three times with ethyl acetate (3×600 ml).The aqueous mixture was made alkaline by adding sodium hydroxide (200ml, 4 M). The aqueous mixture was extracted four times with diethylether (4×500 ml). The product was isolated as free base. Yield 44 g(43%). The corresponding salt was obtained by addition of a diethylether and methanol mixture (9:1) saturated with fumaric acid. Mp 185.0°C.

1-(5-Chloro-3-pyridyl)-piperazine Fumaric Acid Salt (Compound 1A2)

Was prepared according to method A. Mp 195-196° C.

Method B

1-(6-Bromo-5-methoxy-3-pyridyl)-piperazine Fumaric Acid Salt (Compound1B1)

A mixture of 3-chloro-5-methoxypyridine (40.0 g, 0.279 mol), piperazine(48.0 g, 0.557 mol), potassium-tert-butoxide (62.5 g, 0.557 mol) andtetrakis-(triphenylphosphine)palladium (0) (1.6 g, 1.39 mmol) wasrefluxed for 2 hours. The workup procedure was performed according tomethod A. 1-(5-Methoxy-3-pyridyl)-piperazine fumaric acid salt wasisolated as intermediate product. Yield 22.6 g (26%). A mixture of1-(5-methoxy-3-pyridyl)-piperazine fumaric acid salt (23.1 g, 74.7mmol), aqueous sodium hydrogen carbonate (224 ml, 1 M),di-tert-butyldicarbonate (16.3 g, 74.7 mmol) and dichloromethane (200ml) was stirred at room temperature for 1 hour. The phases wereseparated. The organic phase gave4-tert-butoxycarbonyl-1-(5-methoxy-3-pyridyl)-piperazine in quantitativeyield. N-Bromosuccinimide (1.82 g, 10.2 mmol) was added to a mixture of4-tert-butoxycarbonyl-1-(5-methoxy-3-pyridyl)-piperazine (3.0 g, 10.2mmol) and acetonitrile (50 ml) at 0° C. The reaction was allowed toreach room temperature and was stirred for 2 hours. Aqueous sodiumhydroxide (100 ml, 4 M) was added followed by extraction twice withethyl acetate (2×100 ml). Chromatography on silica gel with ethylacetate:petroleum (1:3) gave4-tert-butoxycarbonyl-1-(6-bromo-5-methoxy-3-pyridyl)-piperazine as freebase. Yield 2.6 g, 68%. This compound (2.32 g, 6.23 mmol) wasdeprotected by stirring with a mixture of trifluoroacetic acid (4.8 ml)and dichloromethane (30 ml) for 6 hours. The mixture was evaporated, andaqueous sodium hydroxide (100 ml, 1 M) was added. The mixture wasextracted three times with ethyl acetate (3×100) and gave the titlecompound as the free base. The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid in quantitative yield. Mp 202-218° C.

1-(6-Iodo-5-methoxy-3-pyridyl)-piperazine Fumaric Acid Salt (Compound1B2)

Was prepared according to method B from1-(5-methoxy-3-pyridyl)-piperazine. Using N-iodo succinimide instead ofN-bromo succinimide. Mp 209.5° C.

1-(6-Bromo-3-pyridyl)-piperazine Fumaric Acid Salt (Compound 1B3)

Was prepared according to method B from 1-(3-pyridyl)-piperazine. Mp170.8-171.6° C.

1-(6-Bromo-5-chloro-3-pyridyl)-piperazine Fumaric Acid Salt (Compound1B4)

Was prepared according to method B from1-(5-chloro-3-pyridyl)-piperazine. Mp 199.6-200.2° C.

1-(5,6-Dibromo-3-pyridyl)-piperazine Fumaric Acid Salt (Compound 1B5)

Was prepared according to method B from1-(5-bromo-3-pyridyl)-piperazine. Mp 199.5° C.

1-(5-Bromo-6-chloro-2-pyrazinyl)-piperazine Fumaric Acid Salt (Compound1B6)

Was prepared according to method B from1-(6-chloro-2-pyrazinyl)-piperazine. Mp 185.6° C.

1-(6-Bromo-5-etynyl-3-pyridyl)-piperazine Fumaric Acid Salt (Compound1B7)

Was prepared according to method B from1-(5-etynyl-3-pyridyl)-piperazine. Mp 210.4° C.

Method C

1-(5-Bromo-6-chloro-3-pyridyl)-piperazine Fumaric Acid Salt (Compound1C1)

A mixture of 1-(5,6-dibromo-3-pyridyl)-piperazine (1.5 g, 4.7 mmol) andconcentrated hydrochloric acid (30 ml) was stirred at reflux for 52hours. The mixture was evaporated. Aqueous sodium hydroxide (100 ml, 1M) was added followed by extraction with ethyl acetate (2×50 ml). Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Yield 1.0 g (54%).Mp 181.2-185.9° C.

1-(5,6-Dichloro-3-pyridyl)-piperazine Fumaric Acid Salt (Compound 1C2)

Was prepared according to method C from1-(6-bromo-5-chloro-3-pyridyl)-piperazine. Mp 180.3° C.

1-(6-Chloro-3-pyridyl)-piperazine Dihydrochloric Acid Salt (Compound1C3)

Was prepared from 1-(6-bromo-3-pyridyl)-piperazine according to methodC. Mp 271-273° C.

1-(6-Chloro-5-methoxy-3-pyridyl)-piperazine Fumaric Acid Salt (Compound1C4)

Was prepared from 1-(6-bromo-5-methoxy-3-pyridyl)-piperazine accordingto method C. Mp 201.3-201.6° C.

Method D

(±)-3-(2-Benzothienyl)-8-H-8-azabicyclo[3.2.1]oct-2-ene (Compound 1D1)

A mixture of (±)-3-(2-benzothienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (24.4 g, 0.0955 mol), 1-chloroethyl-chloroformate (15.5 ml,0.143 mol) and xylene (200 ml) was heated and stirred at refluxtemperature for 24 hours. Methanol (300 ml) was added followed bystirring and heating at reflux temperature for 22 hours. The mixture wascooled to room temperature and the product was filtered. The crudeproduct was recrystallised from diethyl ether. Yield 16 g (69%). Mp252-259° C.

(±)-3-(2-Benzothienyl)-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene Fumaric AcidSalt (Compound 1D2)

A mixture of (±)-3-(2-benzothienyl)-8-H-8-azabicyclo[3.2.1]oct-2-ene(2.00 g, 8.29 mmol), bromoethane (0.74 ml, 9.94 mmol),diisopropylethylamine (2.9 ml, 16.6 mmol) and dimethylformamide (30 ml)was stirred at 80° C. for 7 hours. Aqueous sodium hydroxide (50 ml, 1 M)was added and the mixture was extracted three times with ethyl acetate(3×50 ml). Chromatography of this crude mixture on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound. The corresponding salt was obtained by addition of a diethylether and methanol mixture (9:1) saturated with fumaric acid. Yield 1.00g, 31%. Mp 176.9° C.

Method E

(±)-8-Allyl-3-(2-benzothienyl)-8-azabicyclo[3.2.1 ]oct-2-ene (Compound1E1))

A mixture of (±)-3-(2-benzothienyl)-8-H-8-azabicyclo[3.2.1]oct-2-ene(2.00 g, 8.29 mmol), 3-bromo-1-propene (0.74 ml, 9.11 mmol),diisopropylethylamine (2.9 ml, 16.6 mmol) and dimethylformamide (30 ml)was stirred at 80° C. for 24 hours. Aqueous sodium hydroxide (50 ml, 1M) was added and the mixture was extracted three times with ethylacetate (3×50 ml). The crude product was solved in diethyl ether (50 ml)and was washed with aqueous sodium hydroxide (50 ml, 1 M). Yield 1.44 g,62%. Mp 60.6-62.6° C.

(±)-8-Allyl-3-[2-(3-bromothienyl)]-8-azabicyclo[3.2.1]oct-2-ene(Compound 1E2)

Was prepared according to method F. The compound was isolated as an oil.

(±)-3-(2-Benzothienyl)-8-cyanomethyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt (Compound 1E3)

A mixture of (±)-3-(2-benzothienyl)-8-H-8-azabicyclo[3.2.1]oct-2-ene(2.00 g, 8.29 mmol), bromoacetonitrile (0.63 ml, 9.11 mmol),diisopropylethylamine (2.9 ml, 16.6 mmol) and dimethylformamide (30 ml)was stirred at 80° C. for 2.5 hour. Aqueous sodium hydroxide (50 ml, 1M) was added and the mixture was extracted three times with ethylacetate (3×50 ml). Chromatography of this crude mixture on silica gelwith dichloromethane:ethyl acetate (1:1) gave the title compound. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Yield 1.00 g, 31%.Mp 176.9° C.

Method F

(±)-3-[2-(3,4-Dibromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt (Compound 1F1)

To a mixture of 3,4-dibromothiophene (11.7 g, 48.4 mmol) andtetrahydrofuran was added at −80° C.: lithiumdiisopropylamide (27 ml, 2M in heptane/tetrahydrofuran/ethylbenzene). The mixture was stirred for1 h at −80° C. Tropinone (6.73 g, 48.4 mmol) solved in tetrahydrofuran(50 ml) was added at −80° C. and was stirred for 1 h at −80° C. Thereaction-mixture was allowed to reach room temperature. Water (10 ml)was added, followed by aqueous sodium hydroxide (50 ml, 1 M). Thetetrahydrofuran was evaporated. The aqueous mixture was extracted withethyl acetate (3×50 ml). The intermediate product: endo &exo-3-[2-(3,4-Dibromo-thienyl)]-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane.To an ice-cool mixture of endo &exo-3-[2-(3,4-dibromothienyl)]-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane(7.40 g, 19.4 mmol) and tetrahydrofuran (100 ml) was added: thionylchloride (25 ml). The mixture was stirred at 66° C. for 2.5 h. Themixture was evaporated and water (100 ml) was added. The mixture wasextracted with diethyl ether (3×100 ml).

Chromatography of this crude mixture on silica gel with dichloromethane,methanol and conc. ammonia (89:10:1) gave the title compound. Yield 5.26g, 75%. The corresponding salt was obtained by addition of a diethylether and methanol mixture (9:1) saturated with fumaric acid. Mp 176.9°C.

Starting Material:

(±)-8-Methyl-3-trifluoromethanesulfonyl-oxy-8-azabicyclo[3.2.1]oct-2-ene(Compound 1F2)

To 8-methyl-8-azabicyclo[3.2.1]octan-3-one (12.65 g, 90.9 mmol) intetrahydrofuran (300 ml), was added at −70° C.; sodiumbis(trimethylsilyl)amide in tetrahydrofuran (77.5 ml, 77.5 mmol). Thereaction mixture was stirred for 30 min at −70° C.N-phenyl-bis(trifluoromethane-sulfonamide) (32.5 g, 90.9 mmol) intetrahydrofuran (200 ml) was added at −70° C. The reaction mixture wasallowed to reach room temperature slowly and was stirred over night.Aqueous sodium hydroxide (0.1 M, 500 ml) was added and the mixture wasextracted twice with ethyl acetate (200 ml). Chromatography on silicagel with dichloromethane and 10% ethanol as solvent gave the titlecompound as an oil. Yield 16.2 g, 45%.

(±)-3-(5-Indolyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound 1F3)

A mixture of(±)-8-methyl-3-trifluoromethanesulfonyl-oxy-8-azabicyclo[3.2.1]oct-2-ene(3.37 g, 12.4 mmol), 5-indolylboronic acid (2.00 g, 12.4 mmol), lithiumchloride (1.58 g, 37.3 mmol), tetrakistriphenylphosphinepalladium (0)(0.43 mg, 0.4 mmol), potassium carbonate (5.14 g, 37.3 mmol),1,3-propandiol (2.84 g, 37.3 mmol) and 1,2-dimethoxyethane (40 ml) wasstirred and heated at reflux for 20 hours. Aqueous sodium hydroxide (100ml, 1 M) was added. The mixture was extracted twice with diethyl ether.Chromatography of this crude mixture on silica gel with dichloromethane,methanol and conc. ammonia (89:10:1) gave the title compound. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Yield 130 mg, 3.0%.Mp 167.4-178.0° C.

Method G

1-(6-Phenyl-3-pyridazinyl)-piperazine Fumaric Acid Salt (Compound 1G1)

A mixture of 3-chloro-6-phenyl-pyridazine (1.0 g, 5.25 mmol), piperazine(2.26 g, 26.2 mmol) and toluene (50 ml) was stirred at reflux overnight.The pH was adjusted to 6 with aqueous hydrochloric acid (1 M) and theaqueous phase was washed with methylene chloride (3×50 ml). Aqueoussodium hydroxide (100 ml, 2 M) was added. The mixture was extracted withmethylene chloride (3×50 ml). The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Yield 1.0 g, 53%. Mp 196.4-199.1° C.

1-(6-Chloro-2-pyrazinyl)-piperazine Hydrochloric Acid Salt (Compound1G2)

Was prepared according to method G. Mp 285.7° C.

1-(6-Chloro-3-pyridazinyl)-piperazine Fumaric Acid Salt (Compound 1G3)

Was prepared according to method G. Mp 193° C.

1-(6-Iodo-3-pyridazinyl)-piperazine Fumaric Acid Salt (Compound 1G4)

Was prepared according to method G. Mp 187-190° C.

1-[6-(1-Benzimidazolyl)-3-pyridazinyl]-piperazine Fumaric Acid Salt(Compound 1G5)

Was prepared according to method G. Mp 217.0° C.

1-(2-pyrazinyl)-piperazine Fumaric Acid Salt (Compound 1G6)

Was prepared from 1-(6-Chloro-2-pyrazinyl)-piperazine by hydrogenation,using palladium on carbon as catalyst. Mp 177.1° C.

Method H

1-(6-Chloro-2-pyrazinyl)-4-methyl-piperazine Fumaric Acid Salt (Compound1H1)

1-(6-Chloro-2-pyrazinyl)-piperazine (5.0 g, 25.2 mmol), formaldehyde (37wt %, d=1.083, 38 ml, 0.503 mol) and formic acid (d=1.22, 19 ml, 0.503mol) was stirred at reflux for 6 hours. The mixture was evaporated.Aqueous sodium hydroxide (1 M, 100 ml) was added. The mixture wasextracted with diethyl ether (3×100 ml). Chromatography of this crudemixture on silica gel with dichloromethane, methanol and conc. ammonia(89:10:1) gave the title compound. Yield 3.97 g (74%) The correspondingsalt was obtained by addition of a diethyl ether and methanol mixture(9:1) saturated with fumaric acid. Mp 176.9° C.

Method I

1-(6-Phenyl-3-pyridyl)-piperazine Fumaric Acid Salt (Compound 1I1)

A mixture of 1-(6-bromo-3-pyridyl)-4-tert-butoxycarbonylpiperazine (1.0g, 2.9 mmol), phenyl boronic acid (1.06 g, 8.8 mmol), aqueous potassiumcarbonate (4.3 ml, 8.7 mmol), water (4.3 ml), isopropanol (0.66 ml, 8.7mmol), 1.2-dimethoxyethane (10 ml) and palladium (0) tetrakistriphenylphosphine (66 mg, 0.058 mmol) was stirred at reflux for 4 days.Aqueous sodium hydroxide (50 ml) was added and the mixture was extractedwith methylene chloride (3×50 ml). Chromatography of this crude mixtureon silica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave 1-(6-phenyl-3-pyridyl)-4-tert-butoxycarbonylpiperazine. Theintermediate (0.80 g, 2.4 mmol), trifluoroacetic acid (1.8 ml, 23.6mmol) and dichloromethane (10 ml) was stirred for 1.5 hour. The mixturewas evaporated. Aqueous sodium hydroxide (50 ml, 1 M) was was added andthe mixture was extracted with diethyl ether (3×50 ml). Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Mp 203-204° C.

1-(5-Chloro-6-phenyl-3-pyridyl)-piperazine Fumaric Acid Salt (Compound1I2)

Was prepared according to method I from1-(6-bromo-5-chloro-3-pyridyl)-piperazine. Mp 181.6-185.4° C.

Method J

1-(5-chloro-6-methyl-3-pyridyl)-4-tert-butoxycarbonyl-piperazine(Compound 1J1)

A mixture of1-(6-bromo-5-chloro-3-pyridyl)-4-tert-butoxycarbonyl-piperazine (2.0 g,5.3 mmol), tetramethyltin (1.9 g, 10.6 mmol),palladium-di-(triphenylphosphine (0.19 g, 0.26 mmol) anddimethylformamide (2 ml) was stirred at 160° C. in a sealed vesselovernight. The mixture was stirred in conc. hydrochloric acid (30 ml) atreflux for 15 min. The mixture was evaporated. Aqueous sodium hydroxide(50 ml, 1 M) was added and the mixture was extracted withdichloromethane (3×50 ml). Chromatography of this crude mixture onsilica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave the title compound. Yield 0.70 g (43%). The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 178.1-180.5° C.

Method K

1-(5-Etynyl-3-pyridyl)-piperazine Fumaric Acid Salt (Compound 1K1)

A mixture of 1-(5-bromo-3-pyridyl)-4-tert-butoxycarbonyl-piperazine(53.5 g, 0.156 mol), potassium carbonate (54.0 g, 0.391 mol), copper (I)iodide (5.96 g, 31.3 mmol), palladium on carbon (20.0 g, 5%, 50% water),triphenylphosphine (4.1 g, 15.6 mmol), 2-methyl-3-butyn-2-ol (131.5 g,1.56 mol) and dioxane (300 ml) was stirred at reflux for 10 days. Thecrude mixture was filtered through celite. Chromatography of this crudemixture on silica gel with ethyl acetate:petroleum (1:3) gave thecorresponding alcohol. The intermediate (27.4 g, 79.3 mmol), sodiumhydride (0.57 g, 23.8 mmol) and toluene (200 ml) was stirred at reflux 2days. Chromatography of this crude mixture on silica gel with ethylacetate:petroleum (1:3) gave the corresponding1-(5-etynyl-3-pyridyl)-4-tert-butoxycarbonyl-piperazine. Yield 16.6 g,73%. The protecting group was removed by stirring1-(5-etynyl-3-pyridyl)-4-tert-butoxycarbonyl-piperazine (1.02 g, 3.55mmol), trifluoroacetic acid (2.7 ml, 35.5 mmol) and dichloromethane (10ml) overnight. The mixture was evaporated. Aqueous sodium hydroxide (50ml, 1 M) was added and the mixture was extracted with dichloromethane(3×50 ml). Chromatography of this crude mixture on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound. Yield 0.66 g (99%). The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Mp 175.1° C.

Example 2 Preparatory Example General

All reactions involving air sensitive reagents or intermediates wereperformed under nitrogen and in anhydrous solvents. Magnesium sulphatewas used as drying agent in the workup-procedures and solvents wereevaporated under reduced pressure.

9-Methyl-3,9-diazabicyclo-[4.2.1]-nonane

was prepared according to [Michaels R J & Zaugg H E; J. Org. Chem. 196025 637].

(±)3-(2-Naphthalyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane FumaricAcid Salt (Compound 2A)

A mixture of 2-bromonaphtalene (5.0 g; 24.1 mmol),9-Methyl-3,9-diazabicyclo-[4.2.1]-nonane (3.38 g; 24.1 mmol) andpalladacycle (0.045 g; 0.048 mmol) [Angew. Chem. Int. Ed. Engl. 1995 341844] was stirred for two days at 150° C. Sodium hydroxide (50 ml; 1 M)was added at room temperature. The mixture was extracted with diethylether (2×100 ml). Chromatography on silica gel with dichloromethane,methanol and conc. ammonia (89:10:1) gave the title compound. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Yield 0.30 g; 3%.Mp. 173-174° C.

(±)3-(2-Quinolinyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane FumaricAcid Salt (Compound 2B)

A mixture of 2-chloroquinoline (5.0 g; 30.6 mmol) and9-methyl-3,9-diazabicyclo-[4.2.1]-nonane (3.38 g; 24.1 mmol) was stirredin the absence of solvent for 4 hours at 140° C. Sodium hydroxide (50ml; 1 M) was added at room temperature. The mixture was extracted withdiethyl ether (2×100 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound. The corresponding salt was obtained by addition of a diethylether and methanol mixture (9:1) saturated with fumaric acid. Yield 5.2g; 44%. Mp. 173.0-174.2° C.

Method A

(±)3-(3,4-Dichlorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonaneFumaric Acid Salt (Compound 2A1)

A mixture of 1-bromo-3,4-dichlorobenzene (6.65 g; 29.6 mmol) and9-Methyl-3,9-diazabicyclo-[4.2.1]-nonane (5.0 g; 35.5 mmol),potassium-tert-butoxide (6.64 g; 59.2 mmol), tetrakis triphenylphosphinepalladium (0) (1.0 g; 0.88 mmol) and 1,2-dimethoxyethane was stirredovernight. Sodium hydroxide (50 ml; 1 M) was added at room temperature.The mixture was extracted with ethyl acetate (2×40 ml). Chromatographyon silica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave the title compound, Yield 2.41 g; 29%. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp. 114.4° C.

(±)3-(6-Quinolinyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane FumaricAcid Salt (Compound 2A2)

Was prepared according to method A, using 6-chloroquinoline as startingmaterial and palladacycle [Angew. Chem. Int. Ed. Engl. 1995 34 1844],palladium acetate and 2-biphenyl-di-tert-butylphosphine as catalyst. Mp.164-166° C.

(±)3-(4-Fluorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane FumaricAcid Salt (Compound 2A3)

Was prepared according to method A. This product was separated from areaction-mixture of3-(3-fluorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane and3-(4-fluorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane. Mp 123.7°C.

(±)3-(3-Fluorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane FumaricAcid Salt (Compound 2A4)

Was prepared according to method A. This product was separated from areaction-mixture of3-(3-fluorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane and3-(4-fluorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane. Mp 138.6°C.

(±)3-(4-Trifluoromethoxyphenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane(Compound 2A5)

Was prepared according to method A. This product was separated from areaction-mixture of3-(3-trifluoromethoxyphenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonaneand3-(4-trifluoromethoxy-phenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonaneThe product was isolated as an oil.

(±)3-(3-Trifluoromethoxphenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane(Compound 2A6)

Was prepared according to method A. This product was separated from areaction-mixture of3-(3-trifluoromethoxyphenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonaneand3-(4-trifluoromethoxyphenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane.The end product was isolated as an oil.

(±)3-(Phenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane Fumaric Acid Salt(Compound 2A7)

Was prepared according to method A. Mp 143.9° C.

Method B

(±)3-(3,4-Dichlorophenyl)-9-H-3,9-diazabicyclo-[4.2.1]-nonane FumaricAcid Salt (Compound 2B1)

A mixture of3-(3,4-Dichlorophenyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane (0.50 g;1.8 mmol), 1-chloroethyl-chloroformate (0.63 g; 4.4 mmol) and xylene (10ml) was stirred at reflux for 24 h, methanol (10 ml) was added and themixture was stirred at reflux for 5 hours. Sodium hydroxide (50 ml; 1 M)was added at room temperature. The mixture was extracted with ethylacetate (2×40 ml). Chromatography on silica gel with dichloromethane,methanol and conc. ammonia (89:10:1) gave the title compound. Yield 0.14g; 29%. The corresponding salt was obtained by addition of a diethylether and methanol mixture (9:1) saturated with fumaric acid. Mp. 222.3°C.

3-[(5-Chloropyrid-3-yl)-5-oxyethoxypyrid-3-yl]-9-Methyl-3,9-diazabicyclo-[4.2.1]-nonane(Compound 2B2), andO,O″-bis-[5-(9-Methyl-3,9-diazabicyclo-[4.2.1]-nonan-3-yl)-3-pyridyl]-ethyleneglycolFumaric Acid Salt (Compound 2B3).

A mixture of O,O′-bis-(5-chloro-3-pyridyl)-ethyleneglycol (2.0 g; 7.0mmol), 9-Methyl-3,9-diazabicyclo-[4.2.1]-nonane (3.9 g; 28.1 mmol),caesium carbonate (4.6 g; 14.0 mmol), palladacycle (0.050 g; 0.053mmol), palladium acetate (0.050 g; 0.22 mmol),2-biphenyl-di-tert-butyl-phosphine (0.05 g; 0.17 mmol) andtri-tert-butylphoshine (0.05 g; 0.25 mmol) was stirred at 130° C.overnight. Aqueous sodium hydroxide (50 ml; 1 M) was added and themixture was extracted five times with diethylether (5×30 ml). The crudemixture was evaporated and purified by chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound (A) as free base. Yield 0.40 g; 20%. Mp. 112-113° C., and (B)yield 0.40 g; 15%. The corresponding salt of B was obtained by additionof a diethyl ether and methanol mixture (9:1) saturated with fumaricacid. Mp. 84-88° C.

O,O″-bis-(5-chloro-3-pyridyl)-ethyleneglycol

A mixture of ethyleneglycol (138.4 g; 2.23 mol) and sodium (12.3 g; 0.53mol) was stirred at 80° C. for 4 hours. 3,5-Dichloropyridine (66.0 g;0.45 mol) and dimethyl sulfoxide (300 ml) was stirred at 110° C. for 10hours. The mixture was allowed to reach room temperature. Aqueous sodiumhydroxide (1 M; 600 ml) was added, the mixture was stirred and filtered.The title compound was isolated as a crystalline product was isolated(8.7 g; 6.8%). Mp. 136-138° C.

Example 3 Biological Activity Mouse Forced Swim Test

Systemic administration of a classical antidepressant (Desipramine)induces an increase in the forced swim distance performed by mice in asmall water pool. The Forced Swim Test therefore is consideredpredictive of a potential antidepressant pharmacological effect.

Female NMRI mice (of 20-25 g) are habituated to the laboratory (a 12hour light/dark cycle) for at least 16 hours before the experiment.

30 minutes after s.c. injection of either vehicle or drug, the mouse isplaced in a glass beaker (d=16 cm; 5000 ml) with water (24° C.) up till10 cm from the top edge. For the subsequent 6 minutes the duration ofimmobility defined as swim speed less than 2.5 cm/minute, and forcedswim distance defined as distance swum with a speed above 5 cm/minute,is recorded. There are 8 mice in each group.

The activity of the mouse is tracked by the View Point system for themeasurement of distance, immobility, and speed.

Time of immobility ±SEM (seconds) and forced swim distance ±SEM (cm) inseconds time intervals are presented and plotted in SigmaPlot. Meantotal immobility time and total swim distance in the time interval60-360 seconds are calculated and presented for each group. The doseshowing significant difference from the vehicle treated group isreported as the Minimal Effective Dose (MED s.c. mg/kg).

1-(6-Chloro-3-pyridyl)-piperazine (Compound 1C3 of Example 1) (0.3, 1,3, 10 mg/kg s.c.) was tested in the mouse Forced Swim Test (mFST) and itdid not affect forced swimming with a 30 minutes pre-treatment. However,the combination of Venlafaxine and Compound 1C3 (1+3; 3+3; 10+1; 10+3mg/kg s.c.) significantly increased the forced swimming in NMRI mice.

Similar effect has been observed with the combination of

Venlafaxine (10 mg/kg sc) and the homopiperazine1-(6-chloro-3-pyridyl)-homopiperazine (0.1, 0.3 mg/kg s.c.) that isdisclosed in WO 99/21834 as Compound 9K; and

Venlafaxine (10 mg/kg sc) and the homopiperazine1-(5-ethynyl-3-pyridyl)-homopiperazine (0.1, 0.3 mg/kg s.c.) that isdisclosed in WO 99/21834 as Compound 12J; and

Venlafaxine (10 mg/kg sc) and the homopiperazine1-(3-pyridyl)-homopiperazine (0.1, 0.3 mg/kg s.c.) that is disclosed inWO 99/21834 as Compound 1F.

1. 1-(5,6-Dibromo-3-pyridyl)-piperazine, or a pharmaceuticallyacceptable salt thereof.
 2. A pharmaceutical composition comprising atherapeutically effective amount of1-(5,6-dibromo-3-pyridyl)-piperazine, or a pharmaceutically acceptablesalt thereof, together with one or more adjuvants, excipients, carriers,and/or diluents.